The present invention relates to non-psychoactive derivatives of tetrahydro-cannabinol, which exhibit anti-inflammatory, analgesic and leukocyte anti-adhesion activities. The invention includes novel derivatives of (3R,4R)-xcex948-tetrahydrocannabinol-11-oic acids [hereinafter referred to as (3R,4R)-xcex948-THC-11-oic acid], as well as pharmaceutical compositions containing the (3R,4R)-xcex948-THC-11-oic acid derivatives. The invention further includes methods of administering the novel derivatives and pharmaceutical compositions as therapeutic agents in the treatment of pain, tissue inflammation, leukocyte anti-adhesion activity, and the like.
xcex949-Tetrahydrocannabinol [THC], depicted in Formula I under alternate numbering systems, is the major psychoactive constituent of marijuana. 
In addition to mood-altering effects, THC has been reported to exhibit other activities, some of which may have therapeutic value. The potential therapeutic value of THC has led to a search for related compounds which, while devoid of psychoactive effects, retain the activities of potential medicinal value.
Previous work with A8-Tetrahydrocannabinol [(3R,4R) 6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol, hereinafter referred to as xcex948-THC], which is depicted in Formula II below, has indicated that certain derivatives of this compound depicted in Formula II below, may prove clinically useful. The 11-carboxy derivative of xcex948-THC [xcex948-THC-11-oic acid] has been reported to be a non-psychoactive, potent antagonist to endogenous platelet activating factor and, thus, a useful treatment for PAF-induced disorders, such as asthma, systemic anaphylaxis, and septic shock. (U.S. Pat. No. 4,973,603, issued to the present inventor). Another derivative, (3S,4S)-11-hydroxy-xcex948-THC-1xe2x80x2,1xe2x80x2 dimethylheptyl essentially free of the (3R,4R) form, has been reported to possess analgesic and anti-emetic activities. (U.S. Pat. No. 4,876,276).
U.S. Pat. No. 4,847,290, issued to the present inventor, discloses a method of relieving pain in mammals by administering an effective analgesic amount of xcex949-THC-11-oic acid or an analog thereof. These THC derivatives are disclosed to be non-psychoactive metabolites.
U.S. Pat. No. 5,338,753, also issued to the present inventor, discloses (3R,4R)-xcex948-Tetrahydrocannabinol-11-oic acid derivatives having Formula II below: 
wherein R1 is a hydrogen atom, xe2x80x94COCH3 or xe2x80x94COCH2CH3; R2 is a straight chain or branched C5-C12 alkyl, which may have a terminal aromatic ring; a group xe2x80x94(CH2)mxe2x80x94Oxe2x80x94R3, wherein m is an integer from 0 to 7 and R3 is a straight chain or branched alkyl group containing from 1 to 12 carbon atoms, which may have a terminal aromatic ring; or a group CHxe2x80x94(CH3)xe2x80x94(CH2)nxe2x80x94Oxe2x80x94R4, wherein n is an integer from 0 to 7 and R4 is a straight chain or branched alkyl containing from 1 to 12 carbon atoms, which may have a terminal aromatic ring. These xcex948-THC-11-oic acid derivatives are also discussed in an article by Sumner H. Burstein, et al., entitled xe2x80x9cSynthetic Nonpsychotropic Cannabinoids with Potent Antiinflammatory, Analgesic, and Leukocyte Antiadhesion Activities.xe2x80x9d [J. Medicinal Chem., 35(17):3135-3136 (1992).
It is desired, however, to obtain compounds, pharmaceutical compositions, and methods of treatment using compounds substantially devoid of psychoactive effect and with improved therapeutic effects compared to those achieved by conventional xcex948-THC-11-oic acid derivatives, such as those described above. The present invention advantageously affords such compounds, pharmaceutical compositions, and methods of treatment using the compounds and compositions.
The present invention relates to a compound having the formula: 
wherein R1 is hydrogen, xe2x80x94COCH3, or xe2x80x94COCH2CH3; R2 is a branched C5-12alkyl compound which may have a terminal aromatic ring, or a branched xe2x80x94OCHCH3(CH2)malkyl compound which may have a terminal aromatic ring, wherein m is 0 to 7; R3 is hydrogen, a C1-8alkyl compound, or a C1-8alkanol compound; and Y is nil or a bridging group of NH or oxygen; provided that where Y is oxygen and R2 is a branched C5-12alkyl compound, R3 is not xe2x80x94CHCH3.
In one preferred embodiment, R1 is hydrogen, R2 is 1xe2x80x2,1xe2x80x2-dimethylheptyl, and Y is nil. In another preferred embodiment, R2 is a branched xe2x80x94O(CHCH3)(CH2)m alkyl compound terminated with a phenyl ring, wherein m is 0 to 7, and R3 is xe2x80x94CHCH3. This embodiment includes the stereoisomers of such compounds, as well as a racemic mixture or any other percentage mixture of the stereoisomers between 0 and 100 weight percent.
The invention also relates to pharmaceutical compositions that include the compound and its two preferred embodiments described above.
The invention further relates to methods of relieving pain in a mammal by administering to the mammal a therapeutically effective analgesic amount of the compound or pharmaceutical composition, or either of the preferred embodiments, described above.
The invention also relates to methods of relieving inflammation of bodily tissue of a mammal by administering to the mammal a therapeutically effective anti-inflammatory amount of the compound or pharmaceutical composition, or either of the preferred embodiments, described above.